DESCRIPTION (Adapted from the applicant's proposal): This proposal is based on the ongoing research in the sponsor&Otilde;s laboratory on Mycobacterium tuberculosis pathogenesis. This study investigates the role that two-component signal transduction systems play in the virulence of this organism. Specifically, the applicant will characterize the role that the MtrA- MtrB two-component system plays in the survival of M. tuberculosis within the host. Because the response regulator in this system is activated upon infection of macrophages, the hypothesis is that this two-component system (and presumably others as well) may be required for survival within the host. This hypothesis will be tested by: (1) disrupting the mtrA response regulator in M. tuberculosis and testing its effect on virulence within cultured macrophages and within a murine host; (2) identifying and characterizing the genes regulated by MtrA; and (3) determining whether response regulators from other two-component systems are also regulated within phagocytic cells of the host.